6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile is a selective alpha-2 receptor agonist that may be useful for the treatment of various alpha-2 mediated disorders. These disorders include, but are not limited to, irritable bowel syndrome, migraine, chronic tension type headache, ocular hypertension, muscle spasm, muscle hypertonia, attention deficit hyperactivity disorder, sedation, adjunct for anesthesia, anxiety, and Tourette's Syndrome.
The present invention relates to chemical processes suitable for large scale synthesis for making 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile and its preferred anhydrous monoacetate salt. Although the synthesis of 5-(2-imidazolinylamino)-benzimidazoles is generally described, for example, in International Publications WO 95/16685, WO 96/0427, and U.S. Pat. No. 6,066,740, there are many disadvantages in the syntheses described. The most pronounced disadvantage to these previously described methods, is the generation and failure to identify a highly mutagenic side product of the phenazine class of molecules. These previous methods also describe salt forms of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile that exhibit low water solubility, a property that is undesirable for formulation and absorption from the gastrointestinal tract.
In view of the foregoing, there is a need for a synthesis method for 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile that significantly reduces the occurrence of the phenazine impurity and a salt form of 6-[(4,5-Dihydro-1H-imidazol-2-yl)amino-]-7-methyl-1H-benzimidazole-4-carbonitrile that exhibits enhanced water solubility.